Assembly Pattern of Supramolecular Hydrogel Induced by Lower Critical Solution Temperature Behavior of Low-Molecular-Weight Gelator

Article abstract of DOI:10.1021/jacs.9b11290

Although the gelation process and lower critical solution temperature (LCST) behavior are well acknowledged in polymer systems, low-molecular-weight gelators (LMWGs) rarely display LCST behavior during supramolecular gelation. Herein, we report an LMWG system with LCST-type thermoresponsiveness and an LCST-triggered supramolecular gelation process. Temperature plays a crucial role in this system, not only affecting the LCST phase separation but also triggering the gelation process. The backbones (three-dimensional structures) of the resulting hydrogel are the hierarchical assemblies of the LMWG undergoing the LCST phase separation. Hence, the gelation of the LMWG is only realized when the gelation temperature is above the critical transition temperature (T_cloud) of the LCST behavior, which is different from many supramolecular or polymeric hydrogel systems.

Full text of DOI:10.1021/jacs.9b11290

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Article
Assembly Pattern of Supramolecular Hydrogel Induced by Lower
Critical Solution Temperature Behavior of Low-Molecular-Weight Gelator
Shuanggen Wu, Qiao Zhang, Yan Deng, Xing Li, Zheng Luo, Bo Zheng, and Shengyi Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11290 • Publication Date (Web): 11 Dec 2019
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Assembly Pattern of Supramolecular Hydrogel Induced by
Lower Critical Solution Temperature Behavior of Low-Molecu-
lar-Weight Gelator
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Shuanggen Wu,a Qiao Zhang,a Yan Deng,a Xing Li,a Zheng Luo,a Bo Zheng,b* and Shengyi Dong a*
aCollege of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, P. R. China
bKey Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materi-
als Science, Northwest University, Xi’an 710069, P. R. China.
Supporting Information Placeholder
ogy.37-39 However, in polymeric hydrogel systems with LCST be-
ABSTRACT: Although the gelation process and lower critical so-
haviors, the gelation process and LCST behavior are usually two
independent phenomena and do not interfere with each other. In
other words, the formation of hydrogels is not triggered by the
LCST behavior and the critical gelation temperature is always be-
low the Tcloud of LCST behavior. Low-molecular weight-gelators
(LMWGs) are less explored to fabricate LCST-type supramolecu-
lar hydrogels, though they may provide more opportunities for the
design of advanced functional systems with desired structures and
functions.40-42 The restrictions for the exploration of LCST-type su-
pramolecular hydrogels based on LMWGs are: a) it is difficult to
design a small molecule that possesses gelation and LCST capaci-
ties simultaneously and b) the gelation processes of LMWGs are
rich with ambiguity when LCST behavior coexists.
lution temperature (LCST) behavior are well acknowledged in pol-
ymer systems, low-molecular-weight gelators (LMWGs) rarely
display LCST behavior during supramolecular gelation. Herein, we
report an LMWG system with LCST-type thermo-responsiveness
and an LCST-triggered supramolecular gelation process. Temper-
ature plays a crucial role in this system, not only affecting the LCST
phase separation, but also triggering the gelation process. The back-
bones (three-dimensional structures) of the resulting hydrogel are
the hierarchical assemblies of the LMWG undergoing the LCST
phase separation. Hence, the gelation of the LMWG is only realized
when the gelation temperature is above the critical transition tem-
perature (Tcloud) of the LCST behavior, which is different to many
supramolecular or polymeric hydrogel systems.
In general, to display LCST behavior in water, (macro)molecules
are required to form hydrogen bonds with water molecules,
whereas strong water-participant hydrogen bonding is unfavorable
for the supramolecular gelation.43,44 During the gelation process,
gelators aggregate together via intermolecular interactions to form
three-dimensional structures (typical processes of supramolecular
gels; such structures can further assemble to macroscopic gel ma-
terials);45 however, strong gelator–water hydrogen bonding (hydra-
tion effect) can weaken or destroy the intermolecular aggregation.46
Considering the above-mentioned facts, the molecular design is re-
quired to handle the conflict and elegantly balance the two compet-
ing parts. Amphiphilic structures may be ideal candidates to over-
come these problems because their hydrophilic peripheral parts can
interact with water molecules to realize LCST behavior, and the
hydrophobic core of the gelator remains insulated from water mol-
ecules and assembles to form the gel without the interruption by
water molecules. With suitable thermo-responsive segments, the
fabrication of LMWGs-based LCST-type supramolecular hydro-
gels is possible.
INTRODUCTION
Hydrogels are found ubiquitously in biological systems as mul-
tifunctional materials.1-3 Many artificial gelators and gelation strat-
egies have been applied in recent decades to fabricate supramolec-
ular hydrogel materials.4-9 The reversible gel–sol transitions trig-
gered by external stimuli are key steps to realize controlled self-
assembly and functionalization.10-15 The thermo-responsive prop-
erty of hydrogel structures is frequently introduced to artificial hy-
drogel systems to perform gel–sol transitions that are used for drug
release, self-healing, shape memory, and supramolecular adhe-
sion.16-20
Compared with the common gel–sol transitions simply triggered
by heating/cooling, the combination of gelation beahvior and lower
critical solution temperature (LCST)-type thermo-responsiveness
endows hydrogels with a unique property of thermo-responsive-
ness: thermo-responsiveness is achieved and maintained without
gel–sol transitions.21-25 For example, Wang et al. reported poly(N-
isopropylacrylamide) (PNIPAm)-based supramolecular gels with
LCST-type properties, which are available for smart windows.25
Such heating/cooling-induced transparent-turbid transitions of su-
pramolecular gels need a sophisticated molecular design because
supramolecular hydrogels are sensitive to elevated temperature and
would be destroyed at high temperature.26-32 Until now, LCST-type
supramolecular gels are mainly restricted to PNIPAm family, be-
cause PNIPAm and its derivatives have a critical transition temper-
Herein, we report an LMWG system with LCST-type thermo-
responsiveness and an unexpected LCST-induced supramolecular
gelation process. Firstly, the critical transition temperature (Tcloud
)
of the LMWG can be easily modulated, and the hydrogel maintains
its gel morphology over the temperature range being tested. There-
fore, the LCST-type phase behaviors of this system are observed in
both sol and gel states. Secondly, the gelation process of the
LMWG is realized only when the gelation temperature is above
Tcloud. The LCST behavior of the LMWG results in the formation
of visible macroscopic aggregates in sol state, whereas in the sub-
sequent gelation process, these macroscopic aggregates of LMWG
ature (Tcloud) of approximately 30–37 C.33-36 In this temperature
range, supramolecular hydrogels easily maintain the gel morphol-
°
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molecules transform into the three-dimensional structures of hydro-
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gel. Once the gelation temperature is below Tcloud due to the disap-
pearance of macroscopic aggregates, no supramolecular hydrogels
are formed. This LMWG system is different to previously reported
polymeric hydrogels with LCST,21-25 as in this system LCST be-
havior is closely related to the formation of supramolecular hydro-
gels.
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Scheme 1. (a) Chemical structures of LMWG MF and model compounds (TC and MH) and (b) LCST-induced supramolecular gelation:
gelation of MF is only realized when the gelation temperature is above the critical transition temperature (Tcloud) of LCST behavior.
RESULTS AND DISCUSSION
while the hydrophobic tetrafluorobenzene with amide linkers, lo-
cated in the inner layer, controls the aggregation of gelators to re-
alize supramolecular gelation through F–F interactions, π–π stack-
ing, and hydrophobic interactions. MF achieves a balance between
the solubility (hydration effect) and aggregation (gelation process),
according to the solubility test and gelation performances, which is
suitable for the investigation of LCST-triggered supramolecular ge-
lation.47
Monomer design. Benzo-21-crown-7 (B21C7) derivatives are a
new class of LCST molecules and are used in different systems to
facilitate LCST behavior.46 Amphiphilic monomers with two
B21C7 units are designed and synthesized via amidation reactions
from the corresponding benzenedicarboxylic acid (MF in Scheme
1a). Hydrophilic B21C7 units, located on the outer layer, are used
as the thermo-responsive segments to display LCST phase behavior,
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LCST behavior of MF in sol and gel states. The preliminary
Interestingly, the turbid MF solution gradually turns into a turbid
gel, as confirmed by the tube inversion test, scanning electron mi-
croscopic (SEM), transmission electron microscopic (TEM) and
rheological measurements (Figure 1a, middle, Figure S13, S14 and
S15).45,48 Three dimensional networks of fibers were observed
(Figure S13 and S14). The gelation process of MF at 25 °C is slow
(8.0 mg/mL, 9 h). Meanwhile, the turbidity of the sample exists
during the whole gelation process, indicating the concomitant oc-
currence of the LCST behavior. However, no gelation behavior was
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results are observed by heating/cooling MF aqueous solutions di-
rectly. The water solution of MF displays LCST phase separation
when the temperature was elevated/decreased, with reversible
transparent-turbid transitions as typical phenomena (Figure 1a,
left).46 In detail, the transmittance data of MF solutions, shown in
Figures 1b,c, recorded using a UV/Vis spectrometer confirm such
LCST behavior, with a dramatic decrease in transmittance above
Tcloud. The concentration-dependent UV/Vis measurements (Figure
1b, S12) demonstrate a wide distribution of Tcloud from less than
°
observed at 4 °C, 10 C, or 15 °C (8.0 mg/mL, a transparent MF
°
20 °C to more than 50 C (concentration of MF varies from 8.0 to
solution, tested for 72 h), which is in contrast to the common su-
pramolecular gelation processes.40-42 The MF solutions with differ-
ent concentrations (6.0 mg/mL and 12 mg/mL, 10 h and 8 h, re-
spectively) only become hydrogel gels (turbid) when temperatures
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2.0 mg/mL). MF at 8.0 mg/mL has a Tcloud of 18.9 °C upon heating
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or 16.2 C upon cooling (Figure 1c). Further increase in the con-
centration of MF shows only a slight influence on Tcloud and transi-
tion windows (Tcloud of MF at 12 mg/mL is 18.7 °C). The structural
integrity and aggregation reversibility of MF are confirmed by re-
peated heating–cooling cycles (Table S1).
are above Tcloud
.
Figure 1. LCST and gelation behavior of MF: (a) macroscopic LCST-induced gelation of MF sol and gel; (b) concentration-dependent
turbidity curves of MF with heating rate of 1.0 °C/min; (c) heating–cooling cycles of MF (8.0 mg/mL) at sol and gel states, with heating/cool-
ing rate of 1.0 °C/min; (d) temperature-dependent rheology tests of MF gel (8.0 mg/mL); (e) temperature-dependent DLS of MF at a con-
centration of 8.0 mg/mL. Here m-MF, a-MF, and v-MF represent the monomer-type MF, aggregated MF, and visible MF, respectively.
The MF hydrogel of concentration 8.0 mg/mL (prepared at 25 °C)
displays a typical LCST-type behavior after cooling (Figure 1a,
right): the opaque hydrogel gradually turns translucent, and finally
becomes transparent. The entire turbid-transparent transition of the
MF hydrogel is completely reversible. Rheological characteriza-
tion of MF further provides quantitative information on the storage
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moduli (G’) and loss moduli (G’’): G’ values are higher than G’’
LCST-type supramolecular gelation process. The aggregation
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values over the entire experimental range of frequencies and inde-
pendent of frequencies (Figure S13). As shown in Figure 1c, the
Tcloud of the MF hydrogel is close to that of the MF solution at the
same concentration (8.0 mg/mL). The turbidity curves of the MF
solution and MF hydrogel at different heating rates (ranging from
0.1 to 2.0 °C/min, 8.0 mg/mL for MF) are very similar, too. During
processes at different states were easily followed and monitored
because of the slow gelation process of MF at 8.0 mg/mL (25 °C, 9
h). First, the investigations of MF in the sol state were carried out.
Particles with an average size of 3–4 nm in MF solution at temper-
ature below 16 C were clearly noted from the dynamical lighting
scattering (DLS) result (Figure 1e), indicating that MF molecules
°
°
the heating process (15 to 35 C), the hydrogel retains its bulky
exist as monomer types without any aggregation. When the tem-
°
morphology, and no gel–sol transitions or collapsed gels are ob-
served (Figure 1a, right). The rheological tests of MF hydrogels at
variable temperature confirm the stability of hydrogels during the
perature was changed to 18 C, large aggregates with an average
size of approximately 80 nm were recorded. The tyndall effect was
observed at this temperature, whereas no obvious turbidity was vis-
ible to the naked eye. However, when the temperature was in-
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heating process until the temperature exceeds 35 C (Figure 1d).
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Such heating-induced transition from gel to sol is concentration-
dependent. When the concentration of MF was increased from 8.0
mg/mL to 24 mg/mL, the hydrogel is more stable to the elevated
temperature. Macroscopic tests are consistent with the rheological
creased to 19 C, slightly above Tcloud, not only were micrometer-
sized particles detected, but the macroscopic transition from a
transparent solution to a turbid mixture was also observed.
According to the DLS data, it is obvious that an aggregation pro-
cess was induced during heating in the sol state, accompanied with
the size enhancement from invisible monomer-type MF (m-
°
tests: when the temperature was increased from 15 to 35 C, the
hydrogel still kept its bulky morphology (8.0 mg/mL), and only the
light transmittance of the hydrogel gradually decreased.
Figure 2. Concentration-dependent 1H NMR spectra (D2O, 400 MHz, 25 °C) of MF: (a) 1.4 mg/mL, (b) 3.0 mg/mL, (c) 4.0 mg/mL, (d) 5.0
mg/mL, (e) 6.0 mg/mL, and (f) 8.0 mg/mL. Here peaks A and B are in blue and red, respectively.
Figure 3. DOSY spectra (D2O, 400 MHz, 25 °C) of MF: (a) 3.0 mg/mL, (b) 8.0 mg/mL. The same diffusion coefficients are obtained for
residual water molecules.
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MF, < 3–4 nm, Figure S17) to aggregated MF species (a-MF, < 80
nm), and finally to visible particles (v-MF, > 1 µm).
The diffusion coefficient (D) of MF at 3.0 mg/mL is 2.29 × 10-10
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m2/s, corresponding to the size of 1.82 nm.46 Two sets of D were
obtained from the MF spectra at 8.0 mg/mL: 2.29 × 10-10 m2/s (1.82
nm, peak A) and 1.78 × 10-10 m2/s (2.24 nm, peak B). The simula-
tion results demonstrate that the size of a single MF molecule is
smaller than 2.5 nm (Figure S17). The DOSY results indicate that
both peaks A and B belong to the monomer-type MF (m-MF). 1H
NMR spectrum of MF at 15 °C (< Tcloud of MF at 8.0 mg/mL) also
shows peaks A and B, indicating that the occurrence of peak B is
not the result of LCST phase behavior. Hence, these changes of
concentration-dependent NMR spectra can be ascribed to a concen-
tration-induced molecular transformation of MF.
The nuclear magnetic resonance (NMR) experiments of freshly
prepared samples were performed to get further insights into the
gelation process. The concentration of the LMWG is an important
factor that affects the gelation process and the property of the su-
pramolecular gel. During the concentration-dependent NMR tests,
all MF samples were in the sol state. When the concentrations of
MF samples were between 1.4 mg/mL and 5.0 mg/mL, no remark-
able changes in NMR spectra were observed because no apparent
chemical shifts or new peaks emerged (Figure 2, S16). Different
NMR spectra were obtained when the concentrations of MF sam-
ples were further increased. With protons Ha (-CONH2CH2-) as an
example (Figure 2), the former single peak of Ha split into two sets
(peaks A and B) when the MF concentration varied to 6.0 mg/mL
and 8.0 mg/mL.
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During the concentration-dependent and DOSY NMR tests, all
MF samples were in sol state. The time-/temperature-dependent
NMR tests of MF were carried out to monitor the LCST-induced
supramolecular gelation (Figure 4, S18–24), respectively. With re-
sidual water as the standard in the time-dependent NMR spectra,
the normalized intensity of MF was plotted. As shown in Figure
The diffusion ordered spectroscopy (DOSY) experiments of MF
(3.0 mg/mL and 8.0 mg/mL) were carried out at 25 °C (Figure 3).
1
Figure 4. (a) Partial time-dependent H NMR spectra (D2O, 400 MHz, 25 °C) of MF; (b) Partial temperature-dependent 1H NMR spectra
(D2O, 400 MHz) of MF. The concentrations of MF for (a) and (b) are 8.0 mg/mL. Here peaks A and B (m-MF) are in blue and red,
respectively. (c) Normalized intensity of m-MF (peaks A and B in Figure 4a).
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4c, the intensity of m-MF (the total intensities of peaks A and B)
on the structures of PNIPAm (cross-linked polymers). LCST be-
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rapidly decreases during first 9 h, then gradually reaches equilib-
rium. This observation indicates that more and more MF molecules
are not detected during the time-dependent NMR tests.
Two possibilities are envisioned to explain the disappearance of
MF molecules in the NMR spectra:
havior of PNIPAm usually takes place after the formation of hy-
drogels.25,26
Generally, hydrogels consist of two parts: solid-type three-di-
mensional structures (backbones of hydrogels, NMR undetectable)
and solution-type entrapped solvents and LMWGs (sol parts of hy-
drogels, NMR detectable). In the sol part of the hydrogel of MF,
the concentration of entrapped MF molecules is only 4.0 mg/mL
(Figure S28), which is only half of the initial concentration of MF
(8.0 mg/mL of MF when preparing the hydrogel sample), indicat-
ing that the concentration of MF in three-dimensional structures is
much higher than that in the sol part. Based on these information,
it is highly possible that v-MF species induced by LCST behavior
can further self-assemble into the solid-parts (NMR undetectable
three-dimensional structures) of hydrogels (Possibility B, induced
by the gelation process), and the rest of MF molecules are en-
trapped in the sol-parts (NMR detectable).45,47
As mentioned before, two types of MF species are identified: m-
MF (peaks A and B, NMR detectable) and v-MF (visible but NMR
undetectable). Corresponding peaks in DLS of these species are of
sizes below 3–4 nm (m-MF) and above 1 µm (v-MF), respectively.
In this LMWG system, temperature orchestrates a two-step hierar-
chical assembly, the LCST behavior and the gelation process. Dur-
ing the gelation process, the LCST behavior of MF is crucial in
realizing the gelation process because the backbones of hydrogels
are comprised of LCST-induced aggregation of v-MF. In this MF
hydrogel system, these NMR undetectable v-MF aggregates be-
come the turbid phase and the solid-type backbones of supramolec-
ular hydrogels. m-MF molecules are entrapped in hydrogels as the
sol part. Compared with some reported supramolecular polymer
gels, MF hydrogels are non-viscous (because no polymerization
process occurred) but with good mechanical strengths (G’ up to 3
× 103 Pa was observed). MF hydrogels at low temperature have a
good light transmittance (Table S1).
(A) In our previous work, we have found that micrometer-sized
aggregates are NMR undetectable and phase-separated from the
46
LCST solution when temperature is above Tcloud
.
Based on the
DLS results and our previous work, the appearance of NMR unde-
tectable MF molecules may be ascribed to the formation of mi-
crometer-sized aggregates (v-MF, detected by DLS, > 1 µm) that
were phase separated from the MF NMR samples.
(B) During the time-dependent NMR tests, the NMR sample so-
lution (8.0 mg/mL) gradually changed into a mixture of gel and sol,
then completely into gel state. The MF molecules may assemble
into the three-dimensional structures of hydrogels (solid parts of
hydrogels) that are also NMR undetectable as proved by some re-
ported work.45,49,50
TC and MH are analogues of MF and are used as control com-
pounds to evaluate the possibilities for the disappearance of MF
molecules in NMR spectra (Scheme 1 and Figure S25–27).46 TC
and MH display LCST behavior; however, they cannot form hy-
drogels at either low temperature or above Tcloud. Both TC and MH
show decreased intensities of NMR signals when the temperature
is above Tcloud as monitored by NMR (Figure S27).46 Without the
disturbance of the formation of three-dimensional structures of hy-
drogels, the disappearance of TC or MH molecules in NMR spec-
tra is ascribed to the formation of micrometer-sized aggregates
(phase-separated from the LCST solution upon heating).46 Consid-
ering the large aggregates of v-MF observed in DLS tests and the
phase-separation of MF sample during time-dependent NMR tests,
it can be speculated that large v-MF aggregates are responsible for
the disappearance of MF molecules in NMR spectra when the tem-
perature was above Tcloud (Possibility A, induced by LCST behav-
ior).
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CONCLUSIONS
However, this explanation only describes half of the picture. Dif-
ferent NMR changes were observed in the temperature-dependent
NMR spectra of MF (in sol state without any gelation behavior,
Figure 4b, S21–24) compared to that of the time-dependent NMR
spectra (with gelation behavior). As temperature gradually in-
In conclusion, we report the LCST-induced supramolecular ge-
lation process of a low-molecular-weight gelator MF. The reversi-
ble transparent-turbid transitions occurred in both sol and gel states.
Different types of MF aggregates were observed during the LCST-
induced gelation process. The LCST behavior of this hydrogel sys-
tem plays a key role in the supramolecular gelation by forming
macroscopic backbones of hydrogels, which is rarely observed in
polymeric or supramolecular hydrogel systems. The macroscopic
aggregates induced by the LCST phase separation behavior trans-
form into the three-dimensional structures of hydrogels. This re-
search not only proves the feasibility of LMWGs in realizing the
LCST-type thermo-responsiveness besides acrylamide-containing
thermo-responsive polymers, but also provides a clear view of the
LCST-type gelation process. Furthermore, this new class of
thermo-responsive LMWGs provides different insights into the ge-
lation mechanism of supramoelcular hydrogels and represents a
new choice of the design of thermo-sensitive supramolecular sys-
tem.
°
°
creased from 40 C to 70 C, new proton peaks appear in the tem-
perature-dependent NMR spectra of MF, as shown in Figure 4b.
°
As mentioned above, the MF hydrogels are stable below 35 C
(Figure 1e, 8.0 mg/mL), hence during this temperature range, no
gel formation was possible. These newly emerging peaks were also
found in the temperature-dependent NMR spectra of MH and TC
(Figure S27). However, no changes were observed from the time-
dependent NMR spectra of MH or TC (Figure S25, 25 °C), which
is different to MF (Figure 4a).46 This information indicates that
without gel formation (above 40 °C), MF behaves the same as pure
LCST systems like MH or TC. While once gel formation occurred
°
(25 C), LCST behavior of MF is not the same as that of MH or
TC.46
As mentioned above, during the gelation tests, we have found
that the NMR sample solution (8.0 mg/mL) failed to form hydrogel
°
°
°
when the temperature was set at 15 C, 10 C, or 4 C (no LCST
behavior). In additional, MF solutions with lower concentrations
(1.0 mg/mL or 3.0 mg/mL, Figures S18 and S19) showed neither
apparent changes during time-dependent NMR tests nor become
hydrogels. These observations indicated that once v-MF species
were absent due to the lower temperature or concentration, MF
could not assemble into three-dimensional structures of hydrogels.
Such observations are quite different to PNIPAm hydrogels. In
these polymeric systems, the formation of hydrogels is dependent
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization and NMR spectra for
obtained compounds and other materials (PDF)
AUTHOR INFORMATION
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(18) Lu, C.-H.; Guo, W.; Hu, Y.; Qi, X.-J.; Willner, I. Multitriggered
Shape-Memory Acrylamide-DNA Hydrogels. J. Am. Chem. Soc. 2015, 137,
15723–15731.
(19) Jia, Y.-G.; Zhu, X. Self-Healing Supramolecular Hydrogel Made of
Polymers Bearing Cholic Acid and β-Cyclodextrin Pendants. Chem. Mater.
2015, 27, 387–393.
Corresponding Author
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* dongsy@hnu.edu.cn
* zhengbo@nwu.edu.cn
ORCID
4
5
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8
9
(20) Zhang, M.; Xu, D.; Yan, X.; Chen, J.; Dong, S.; Zheng, B.; Huang, F.
Self-Healing Supramolecular Gels Formed by Crown Ether Based Host–
Guest Interactions. Angew. Chem. Int. Ed. 2012, 51, 7011–7015.
(21) Fernández-Castaño Romera, M.; Göstl, R.; Shaikh, H.; ter Huurne,
G.; Schill, J.; Voets, I. K.; Storm, C.; Sijbesma, R. P. Mimicking Active
Biopolymer Structures with a Synthetic Hydrogel. J. Am. Chem. Soc. 2019,
141, 1989–1997.
(22) Karimi, M.; Zangabad, P. S.; Ghasemi, A.; Amiri, M.; Bahrami, M.;
Malekzad, H.; Asl, H. G.; Mahdieh, Z.; Bozorgomid, M.; Ghasemi, A.;
Boyuk, M. R. R. T.; Hamblin, M. R. Temperature-Responsive Smart
Nanocarriers for Delivery Of Therapeutic Agents: Applications and Recent
Advances. ACS Appl. Mater. Interfaces 2016, 8, 21107–21133.
(23) Hapiot, F.; Menuel, S.; Monflier, E. Thermoresponsive Hydrogels in
Catalysis. ACS Catal. 2013, 3, 1006–1010.
(24) Kitazawa, Y.; Ueki, T.; McIntosh, L. D.; Tamura, S.; Niitsuma, K.;
Imaizumi, S.; Lodge, T. P.; Watanabe, M. Hierarchical Sol–Gel Transition
Induced by Thermosensitive Self-Assembly of An ABC Triblock Polymer
in an Ionic Liquid. Macromolecules 2016, 49, 1414–1423.
(25) Wang, S.; Xu, Z.; Wang, T.; Xiao, T.; Hu, X.-Y.; Shen, Y.-Z.; Wang,
L. Warm/Cool-Tone Switchable Thermochromic Material for Smart Win-
dows by Orthogonally Integrating Properties of Pillar[6]Arene and Ferro-
cene. Nat. Commun. 2018, 9, 1737.
(26) Zhang, Z.-X.; Liu, K. L.; Li, J. A Thermoresponsive Hydrogel
Formed from a Star–Star Supramolecular Architecture. Angew. Chem. Int.
Ed. 2013, 52, 6180–6184.
(27) Du, P.; Liu, J.; Chen, G.; Jiang, M. Dual Responsive Supramolecular
Hydrogel with Electrochemical Activity. Langmuir 2011, 27, 9602–9608.
(28) Lorson, T.; Jaksch, S.; Lübtow, M. M.; Jüngst, T.; Groll, J.; Lühmann,
T.; Luxenhofer, R. A Thermogelling Supramolecular Hydrogel with
Sponge-Like Morphology as a Cytocompatible Bioink. Biomacromolecules
2017, 18, 2161–2171.
(29) Görl, D.; Soberats, B.; Herbst, S.; Stepanenko, V.; Würthner, F.
Perylene Bisimide Hydrogels and Lyotropic Liquid Crystals with Temper-
ature-Responsive Color Change. Chem. Sci. 2016, 7, 6786–6790.
(30) Appel, E. A.; Biedermann, F.; Rauwald, U.; Jones, S. T.; Zayed, J.
M.; Scherman, O. A. Supramolecular Cross-Linked Structures via
Host−Guest Complexation with Cucurbit[8]Uril. J. Am. Chem. Soc. 2010,
132, 14251–14260.
(31) Kiyonaka, S.; Sugiyasu, K.; Shinkai, S.; Hamachi, I. First Thermally
Responsive Supramolecular Polymer Based on Glycosylated Amino Acid.
J. Am. Chem. Soc. 2002, 124, 10954–10955.
(32) Liu, J.; Chen, G.; Guo, M.; Jiang, M. Dual Stimuli-Responsive Su-
pramolecular Hydrogel Based on Hybrid Inclusion Complex (HIC). Mac-
romolecules 2010, 43, 8086–8093.
(33) Zhang, X.-Z.; Xu, X.-D.; Cheng, S.-X.; Zhuo, R.-X. Strategies to Im-
prove the Response Rate of Thermosensitive PNIPAAm Hydrogels. Soft
Matter 2008, 4, 385–391.
(34) Rosa, V. R.; Woisel, P.; Hoogenboom, R. Supramolecular Control
over Thermoresponsive Polymers. Mater. Today 2016, 19, 44–55.
(35) Noro, A.; Hayashi, M.; Matsushita, Y. Design and Properties of Su-
pramolecular Polymer Gels. Soft Matter 2012, 8, 6416–6429.
(36) Taylor, M. J.; Tomlins, P.; Sahota, T. S. Thermoresponsive Gels. Gels
2017, 3, 4.
(37) Kawaguchi, H. Thermoresponsive Microhydrogels: Preparation,
Properties and Applications. Polym. Int. 2014, 63, 925–932.
(38) Haq, M. A.; Su, Y.; Wang, D. Mechanical Properties of PNIPAM
based Hydrogels: A Review. Mater. Sci. Eng. C 2017, 70, 842–855.
(39) Gandhi, A.; Paul, A.; Sen, S. O.; Sen, K. K. Studies on Thermorespon-
sive Polymers: Phase Behaviour, Drug Delivery and Biomedical Applica-
tions. Asian J. Pharm. Sci. 2015, 10, 99–107.
(40) Draper, E. R. Adams, D. J. Low-Molecular-Weight Gels: The State
of the Art. Chem. 2017, 3, 390–410.
(41) Estroff, L. A.; Hamilton, A. D. Water Gelation by Small Organic
Molecules. Chem. Rev. 2004, 104, 1201–1218.
(42) Piepenbrock, M.-O. M.; Lloyd, G. O.; Clarke, N.; Steed, J. W. Metal-
and Anion-Binding Supramolecular Gels. Chem. Rev. 2010, 110, 1960–
2004.
(43) Shenoy, S. L.; Painter, P. C.; Coleman, M. M. The Swelling and Col-
lapse of Hydrogen Bonded Polymer Gels. Polymer 1999, 40, 4853–4863.
Shengyi Dong: 0000-0002-8640-537X
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by National Natural Science Foundation
of China (21704024), Huxiang Young Talent Program from Hunan
Province (2018RS3036), the Fundamental Research Funds for the
Central Universities from Hunan University, and the 1000 Talents
Award of Shaan’xi Province (334041900005).
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REFERENCES
(1) Bhattacharya, S.; Samanta, S. K. Soft-Nanocomposites of Nanoparti-
cles and Nanocarbons with Supramolecular and Polymer Gels and Their
Applications. Chem. Rev. 2016, 116, 11967–12028.
(2) Hirst, A. R.; Escuder, B.; Miravet, J. F.; Smith, D. K. High-Tech Ap-
plications of Self-Assembling Supramolecular Nanostructured Gel-Phase
Materials: From Regenerative Medicine to Electronic Devices. Angew.
Chem. Int. Ed. 2008, 47, 8002–8018.
(3) Ma, X.; Zhao, Y. Biomedical Applications of Supramolecular Systems
Based on Host–Guest Interactions. Chem. Rev. 2015, 115, 7794–7839.
(4) Döring, A.; Birnbaum, W.; Kuckling, D. Responsive Hydrogels-Struc-
turally and Dimensionally Optimized Smart Frameworks for Applications
in Catalysis, Micro-System Technology and Material Science. Chem. Soc.
Rev. 2013, 42, 7391–7420.
(5) Foster, J. A.; Parker, R. M.; Belenguer, A. M.; Kishi, N.; Sutton, S.;
Abell, C.; Nitschke, J. R. Differentially Addressable Cavities within Metal-
Organic Cage-Cross-Linked Polymeric Hydrogels. J. Am. Chem. Soc. 2015,
137, 9722–9729.
(6) Zhou, J.; Du, X.; Gao, Y.; Shi, J.; Xu, B. Aromatic-Aromatic Interac-
tions Enhance Interfiber Contacts for Enzymatic Formation of a Spontane-
ously Aligned Supramolecular Hydrogel. J. Am. Chem. Soc. 2014, 136,
2970–2973.
(7) Xu, W.; Song, Q.; Xu, J.-F.; Serpe, M. J.; Zhang, X. Supramolecular
Hydrogels Fabricated from Supramonomers: A Novel Wound Dressing
Material. ACS Appl. Mater. Interfaces 2017, 9, 11368–11372.
(8) Sun, J.-Y.; Zhao, X.; Illeperuma, W. R. K.; Chaudhuri, O.; Oh, K. H.;
Mooney, D. J.; Vlassak, J. J.; Suo, Z. Highly Stretchable and Tough Hydro-
gels. Nature 2012, 489, 133–136.
(9) Ke, H.; Yang, L.-P.; Xie, M.; Chen, Z.; Yao, H.; Jiang, W. Shear-In-
duced Assembly of a Transient yet Highly Stretchable Hydrogel Based on
Pseudopolyrotaxanes. Nat. Chem. 2019, 11, 470–477.
(10) Coates, I. A.; Smith, D. K. Controlled Self-Assembly-Synthetic Tuna-
bility and Covalent Capture of Nanoscale Gel Morphologies. Chem. Eur. J.
2009, 15, 6340–6344.
(11) Zhang, Q.; Qu, D.-H.; Wu, J.; Ma, X.; Wang, Q.; Tian, H. A Dual-
Modality Photoswitchable Supramolecular Polymer. Langmuir 2013, 29,
5345–5350.
(12) Du, X.; Zhou, J.; Shi, J.; Xu, B. Supramolecular Hydrogelators and
Hydrogels: From Soft Matter to Molecular Biomaterials. Chem. Rev. 2015,
115, 13165–13307.
(13) Matsumoto, K.; Sakikawa, N.; Miyata, T. Thermo-Responsive Gels
That Absorb Moisture and Ooze Water. Nat. Commun. 2018, 9, 2315.
(14) Komatsu, H.; Matsumoto, S.; Tamaru, S.; Kaneko, K.; Ikeda, M.;
Hamachi, I. Supramolecular Hydrogel Exhibiting Four Basic Logic Gate
Functions To Fine-Tune Substance Release. J. Am. Chem. Soc. 2009, 131,
5580–5585.
(15) Yan, X.; Xu, D.; Chi, X.; Chen, J.; Dong, S.; Ding, X.; Yu, Y.; Huang,
F. A Multiresponsive, Shape-Persistent, and Elastic Supramolecular Poly-
mer Network Gel Constructed by Orthogonal Self-Assembly. Adv. Mater.
2012, 24, 362–369.
(16) Draper, E. R.; Adams, D. J. How Should Multicomponent Supramo-
lecular Gels Be Characterised? Chem. Soc. Rev. 2018, 47, 3395–3405.
(17) Montero de Espinosa, L.; Meesorn, W.; Moatsou, D.; Weder, C. Bio-
inspired Polymer Systems with Stimuli-Responsive Mechanical Properties.
Chem. Rev. 2017, 117, 12851–12892.
ACS Paragon Plus Environment

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Page 8 of 14
(44) Krieg, E.; Bastings, M. M. C.; Besenius, P.; Rybtchinski, B. Supra-
(48) Yang, L.; Tan, X.; Wang, Z.; Zhang, X. Supramolecular Polymers:
molecular Polymers in Aqueous Media. Chem. Rev. 2016, 116, 2414–2477.
(45) Dong, S.; Luo, Y.; Yan, X.; Zheng, B.; Ding, X.; Yu, Y.; Ma, Z.; Zhao,
Q.; Huang, F. A Dual-Responsive Supramolecular Polymer Gel Formed by
Crown Ether Based Molecular Recognition. Angew. Chem. Int. Ed. 2011,
50, 1905–1909.
(46) Qi, Z.; Chiappisi, L.; Gong, H.; Pan, R.; Cui, N.; Ge, Y.; Bottcher, C.;
Dong, S. Ion Selectivity in Nonpolymeric Thermosensitive Systems In-
duced by Water-Attenuated Supramolecular Recognition. Chem. Eur. J.
2018, 24, 3854–3861.
(47) Dong, S; Leng, J.; Feng, Y.; Liu, M.; Stackhouse, C. J.; Schonhals,
A; Chiappisi, L.; Gao, L.; Chen, W.; Shang, J.; Jin, L.; Qi, Z.; Schalley, C.
A. Structural Water as An Essential Comonomer in Supramolecular
Polymerization. Sci. Adv. 2017, 3, eaao0900.
Historical Development, Preparation, Characterization, and Functions.
Chem. Rev. 2015, 155, 7196–7239.
(49) Hirst, A. R.; Miravet, J. F. Escuder, B.; Noirez, L.; Castelletto, V.;
Hamley, I. W.; Smith, D. K. Self-Assembly of Two-Component Gels: Stoi-
chiometric Control and Component Selection. Chem. Eur. J. 2009, 15, 372–
379.
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(50) Raeburn, J.; Adams, D. J. Multicomponent Low Molecular Weight
Gelators. Chem. Commun. 2015, 51, 5170–5180.
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Scheme 1. (a) Chemical structures of LMWG MF and model compounds (TC and MH) and (b) LCST-induced
supramolecular gelation: gelation of MF is only realized when the gelation temperature is above the critical
transition temperature (Tcloud) of LCST behavior.
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Figure 1. LCST and gelation behavior of MF: (a) macroscopic LCST-induced gelation of MF sol and gel; (b)
concentration-dependent turbid-ity curves of MF with heating rate of 1.0 °C/min; (c) heating–cooling cycles
of MF (8.0 mg/mL) at sol and gel states, with heating/cooling rate of 1.0 °C/min; (d) temperature-
dependent rheology tests of MF gel (8.0 mg/mL); (e) temperature-dependent DLS of MF at a concentration
of 8.0 mg/mL. Here m-MF, a-MF, and v-MF represent the monomer-type MF, aggregated MF, and visible
MF, respectively.
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Figure 2. Concentration-dependent 1H NMR spectra (D2O, 400 MHz, 25 °C) of MF: (a) 1.4 mg/mL, (b) 3.0
mg/mL, (c) 4.0 mg/mL, (d) 5.0 mg/mL, (e) 6.0 mg/mL, and (f) 8.0 mg/mL. Here peaks A and B are in blue
and red, respectively.
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Figure 3. DOSY spectra (D2O, 400 MHz, 25 °C) of MF: (a) 3.0 mg/mL, (b) 8.0 mg/mL. The same diffusion
coefficients are obtained for residual water molecules.
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Figure 4. (a) Partial time-dependent 1H NMR spectra (D2O, 400 MHz, 25 °C) of MF; (b) Partial temperature-
dependent 1H NMR spectra (D2O, 400 MHz) of MF. The concentrations of MF for (a) and (b) are 8.0 mg/mL.
Here peaks A and B (m-MF) are in blue and red, respec-tively. (c) Normalized intensity of m-MF (peaks A
and B in Figure 4a).
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